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BTK kinase activity is dispensable for the survival of diffuse large B-cell lymphoma.
- Source :
-
Journal of Biological Chemistry . Nov2022, Vol. 298 Issue 11, p1-11. 11p. - Publication Year :
- 2022
-
Abstract
- Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phosphotyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W -inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) cells. Paradoxically, we found that DLBCL cells harboring kinase-inactive BTK exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, and optimal cellular growth. Moreover, we determined that DLBCL cells with kinase-inactive BTK remained addicted to BCR signaling and were thus sensitive to targeted BTK degradation by the proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening in DLBCL cells with WT or kinase-inactive BTK, we discovered that DLBCL cells with kinase-inactive BTK displayed increased dependence on Toll-like receptor 9 (TLR9) for their growth and/or survival. Our study demonstrates that the kinase activity of BTK is not essential for oncogenic BCR signaling and suggests that BTK's noncatalytic function is sufficient to sustain the survival of DLBCL. [ABSTRACT FROM AUTHOR]
- Subjects :
- *B cells
*DIFFUSE large B-cell lymphomas
*BRUTON tyrosine kinase
*B cell receptors
Subjects
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 298
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Journal of Biological Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 160600215
- Full Text :
- https://doi.org/10.1016/j.jbc.2022.102555